Investigations on incidence and relevant factors of allergies in 5725 urban pregnant women: a cohort study in China

Background Allergic diseases are highly prevalent in the women of childbearing age. As we know, the immune system could change when pregnancy, which may affect the course of allergic diseases. Meanwhile, they also can affect the course and outcome of pregnancy. The data on incidence of allergies during pregnancy is lacking and conducting clinical trials in pregnant women was limited, therefore, we observed a prebirth cohort to supplement the relevant data and strengthen concerned research conductions. Objective We aim to obtain the incidence of allergies in urban pregnancy and explore the relevant factors of allergic diseases in urban pregnancy. Methods We design a multicenter and prospective cohort in 20 institutions above municipal level which were eligible according to the study design from 14 provinces covering all-side of China. This cohort was conducted from 13+6 weeks of gestation to 12 months postpartum and in our study, we chose the prenatal part to analyze. The outcome was developing allergies during pregnancy, which were diagnosed by clinicians according to the uniform criterion from National Health Commission. All the data was collected by electronic questionnaires through tablet computers. Results The incidence of allergic diseases in urban pregnant women was 21.0% (95%CI 20.0% ~ 22.0%). From social demography data, the history of allergies of pregnant women and their parents had statistical significance(p < 0.01); For exposure to living or working environment, house decoration for less than half a year, exposure to plush toys, disinfectants, insecticides, antihistamines, glucocorticoids, antipyretic analgesics, tocolytic agent and probiotics had statistical significance (all p < 0.05); For psychological status, self-rated depression and anxiety had statistical significance (p = 0.026;p = 0.006). Conclusion The incidence of allergic diseases in urban pregnant women was similar to the former study and kept a medium–high level. The history of allergies of pregnant women and their parents, house decoration time, exposure to plush toys, disinfectants, insecticides, antihistamines, glucocorticoids, antipyretic analgesics, tocolytic agents, probiotics, self-rated depression, and anxiety were relevant factors of allergic diseases during pregnancy.


Introduction
As one of the non-communicable diseases, allergy is dramatically emerging in both developing and developed countries. Allergy is a hypersensitivity reaction initiated by specific immunologic responses against foreign,

Open Access
BMC Public Health *Correspondence: Wang Ailing Ailing@chinawch.org.cn National Center for Women and Children's Health Chinese Center for Disease Control and Prevention, Beijing, China usually harmless, substances. The incidence of allergic diseases is on the rise all over the world and allergies have become a serious public health problem and caused a severe disease burden [1]. Nowadays, around 20% of pregnant women are effected with allergic diseases, especially rhinitis and asthma [2]. Others like atopic dermatitis, allergic conjunctivitis, acute urticaria, food allergy, and drug allergy can also occur frequently in pregnant women. These conditions make pregnancy more complex, for example, women with asthma when pregnant have higher risks of prematurity, small for gestational age (SGA), and neonatal intensive care unit admission [3]. Allergy not only causes long-term immune dysfunction but also has underlying inflammation, which forms the underlying factor for other non-communicable diseases [4]. Recent studies found that maternal nutrition, pollutant particles and smoking or exposure to smoke can influence the incidence of allergy in offspring [5][6][7].
Normally, the risk factors associated with allergic diseases include genetic factors and environmental factors [8]. Previous researches mostly focus on the influence factors of allergic diseases in adults but not pregnancy. To date, there is no comprehensive evidence quantifying the plausibility of the association between developing allergic diseases and influence factors in pregnant women. We conducted a large cohort lasting from November 2017 to July 2020 with the outcomes of infants' food allergies in 20 institutions above municipal level covering 14 provinces in China. And in this article, we explore the detailed relevant factors of allergy in pregnancy, which is part of the large cohort. Particularly, in addition to sociodemographic characteristics, intake of food and possible exposure, we also collect information about psychological status like depression and anxiety.

Study objectives
1.1.1 To master the incidence of various allergies among pregnant women in part urban areas of China; 1.1.2 To know the relevant factors that associated with allergies during pregnancy;

Study sites and participants
According to the geographical and population distribution of China, 20 municipal and provincial maternal and child health hospitals(MCH) from 14 provinces (covering the east, west, north and south) were selected as research institutions, which had the conditions for the diagnosis of allergic diseases, or the ability to be transferred to the local general medical institutions with allergic diagnosis function. Simultaneously, all the MCH institutions could follow up with the study participants standardly in succession. As for the large cohort, sample size was calculated according to the rate of the infant food allergies (8%) cohort. Meanwhile, we used 5-20 times the number of independent variables to be studied and the incidence of allergic rhinitis (30%), asthma (23.2%-32%) and urticaria (20%) in population mentioned in the literature [9][10][11] to verify the sample size. The completed sample size(5725) was representative and met the requirements. Following written informed consent, pregnant women completed the first questionnaire at enrollment in the first trimester of pregnancy (13 +6 weeks). They should have been living in the city where the research institution is located for more than one year and plan to continue to live there for more than two years, therefore, investigators can follow up with them in the third trimester.

Study procedure
After conducting the preliminary trial which selected 3 women in the first trimester and 3 in the third trimester, questionnaires were modified by experts and professors and then administrated to all participating women by trained investigators in both the first trimester (under 13 +6 weeks) and third trimester (between 28 to 32 weeks) face to face. Relevant information contained demographic characteristics, history of allergies, residential and working environment, lifestyle, gestational age, complications of pregnancy, medication and psychological status during pregnancy. The outcome variable is whether the participants developed allergies during pregnancy which were diagnosed by clinicians according to uniform criterion [12][13][14][15][16][17][18]. The first and follow-up investigations were conducted in person at participating hospitals or maternal and child health care institutions covering 14 provinces in China. The detailed procedure was presented in Fig. 1.

Data collecting
Data collection is mainly completed through tablet computers and summarized in a specialized electronic database managed by National Center for women and children's health. With the unified information system, electronic questionnaire and related data entry, storage, logical error correction, data generation, submission and upload procedures were more efficient. All the data was collected by two people who had been trained before.

Statistical analyses
To master the incidence of allergic diseases in pregnant women, we counted occurrence times from the first to third trimesters. Descriptive statistics were used to study the demographic and general information of the participants. χ 2 test and exact Fisher test were used to analyze various factors whether had difference between the allergic group and the control group [19]. The tests were two-tailed with the threshold of significance at P < 0.05, P values less than 0.05 were considered significant. We performed all analyses using STATA 14.0.

Results
A total of 5725 pregnant women were recruited in the study from 20 institutions from 14 provinces of China. Table 1 shows general information of participants and their family, including age, ethnic group, pre-pregnancy body mass index (Pre-BMI), occupation, highest education level, per capita household income, etc.

History of allergies of pregnant women and family members
We also list the history of allergies in pregnant women and their parents in Table 1, mainly about (1) asthma; (2) allergic rhinitis; (3) atopic dermatitis (itchy inflammation of the skin, with a tendency to flare up from time to time); (4) eczema; (5) food allergy; (6) drug allergy; (7) allergic conjunctivitis; (8) Allergic urticaria (9) others, for example, contact dermatitis, ultraviolet allergy (solar dermatitis), allergic cheilitis, allergic purpura, positive skin scratch sign, allergic bronchitis, etc. All these allergic diseases mentioned above were diagnosed by clinician from different departments.

Exposure in residential or working environment of pregnant women
Pregnant women who may expose to the high-risk allergens when working account for 2.9% (167). The allergens generally contained rubber, paints/coatings, adhesives, chemical plastics, pesticides, leather/fur products, while  in living conditions, the decoration, carpet, cooking fuel use, heating, ventilation, home humidity, plants breeding (pollen contact), pets, plush toys, disinfectants, mosquito repellents, insecticides, air fresheners and other substances all had the possibility to cause allergies. The detailed data can be found in Table 1.

Smoking and alcohol use among pregnant women
According to investigations, a total of 936 (16.3%) of 5725 pregnant women were exposed to smoking in their daily life and work environment, which were divided into active smoking and passive smoking. The passive smoking can be found because their husbands, their colleagues, their parents or their other family members were smokers. As for drinking during pregnancy, only 4.9% admitted they had drunk, that's to say 282 pregnant women.

Medication and probiotics intake among pregnant women
We surveyed the using frequency of several medication that have been shown in the literature to have effect on allergies, including antihistamines, antibiotics, glucocorticoids, antipyretic analgesics and progesterone-type tocolytic agent. The results demonstrated that there were 2525 cases (44.1%) of pregnant women who had taken these drugs and 765 (13.4%) who had received probiotics.

Mental state of pregnant women
We use Patient health questionnaire 9(PHQ-9) scale for depression and Generalized anxiety disorder-7(GAD-7) scale for anxiety, each scale was assigned a score according to which the diagnosis and grading of disease were assisted. The occurrence of depression/anxiety in either first or last trimester or both stages was considered as the occurrence of depression/anxiety, and the higher score was regarded as the grading standard when both stages occurred. The score and grading of depression scale and anxiety scale are shown in Table 2.
According to the PHQ-9, 3955 pregnant women (69.1%) with different degrees of depression were found, mild depression was the highest (76.2%); The results of the GAD-7 showed that 2032 pregnant women (35.5%) had different degrees of anxiety during pregnancy, and mild anxiety accounted for the highest proportion (85.8%). More details were found in Table 3.

Incidence of allergic diseases in pregnant women
Among 5725 participants who have been followed up completely, 1200 pregnant women developed allergies that were diagnosed by clinician in anytime of pregnancy. The incidence was 21%(95%Confidence Intervals[CI]:20.0% ~ 22.0%). As shown in Table 4, the number, incidence and proportion of allergies in pregnant women at different stages of pregnancy were various. We found the proportion of pregnant women with allergy only in the third trimester was the highest (53.3%). In addition, the incidence of different categories of allergies in pregnancy was not unified. We can see the highest three were 519 cases of allergic rhinitis (9.07%), 327 cases of eczema (5.71%) and 158 cases of atopic dermatitis (2.76%), more details are listed in Fig. 2. Table 5 depicts single or combined occurrence of allergies during pregnancy, results indicate that single occurrence was most common, accounting for 18.6% of all allergic cases.

Correlation analysis between risk factors and allergies in pregnant women
We divided two groups by whether participants had allergies during pregnancy, which were allergic group (1200 cases) and control group (4525 cases). By univariate analysis of χ 2 test and Fisher's Exact Test, we analyzed differences of factors between two groups and explored whether the affect from above factors may change the incidence of allergies during pregnancy. The results showed that relevant factors contains that the history of allergies of pregnant women and their parents, house decoration time, exposure to plush toys, disinfectants, insecticides, antihistamines, glucocorticoids, antipyretic analgesics, tocolytic agent, probiotics, self-rated depression and anxiety. There were statistically significant differences between the two groups (P < 0.05) when analyzing those influence factors (Table 6).

Discussion
Nowadays, the health quality of pregnant women and their offspring were attached high importance as it related to health development of the two generations. This study kept attention to allergic diseases during Table 2 The score and grading of PHQ-9 and GAD-7   pregnancy, the relevant data of which was nearly scarce in China and even Asia. According to the results, we found 1200 participants (21%) developed allergies during pregnancy in urban area, which was similar to the result of Isabella et al. [2] from secondary publication. The highest three kinds of allergies were allergic rhinitis(9.07%), eczema(5.71%) and atopic dermatitis(2.76%). The incidence of allergic rhinitis was lower than in recent surveys, Orban et al. [20]conducted and concluded the pregnant rhinitis was 18% ~ 30%, while in Turkish [21] women was 17.17%. Gestational itchy dermatoses which contained eczema and atopic dermatitis are relatively common, with eczema being diagnosed in 36% to 49% of all pregnancy dermatoses [22]. Our findings showed the incidence of asthma during pregnancy was 0.3%, which was quite different from a worldwide survey that explained asthma affects up to 13% of pregnancies worldwide [23] and asthma prevalence is increasing [24,25]. The possible reason for the discrepancy between our findings and other study was that diagnostic criteria and survey methods had differences. In the light of our study design, we utilized special electronic questionnaires and a unified electronic database which could ensure the integrity and authenticity of data, simultaneously, the large sample size covering 14 provinces in China could almost represent the race/ethnicity, living habits and environment of the Chinese urban females.
Our study could not only supplement data on allergies of urban pregnant women but increase the knowledge and understanding of the relevant factors of allergic diseases during pregnancy. Our findings on the correlation between various factors and allergies during pregnancy are in accordance with the previous studies, for example, the history of allergies was confirmed in a cohort study in a hospital in the USA [26]. Environment elements particularly indoor substances (decorations, disinfectants, insecticides, et. al), medication (glucocorticoids, antipyretic analgesics, tocolytic agent, et. al), and psychological stress were mentioned [10,27,28] and demonstrated association with allergies. These findings will enable physicians to better counsel families with allergic diseases and enable researchers to develop targeted prevention strategies. We also found drinking had influence on allergies but exposure to smoke (passive or active) had no significance, which contradicted the results from Pali-Schöll et al. [8] that exposure to smoke was a risk factor of allergy. Even so, excessive drinking or smoking was not recommended during pregnancy, which may lead to a variety of chronic diseases but not limited to allergies. Recently, probiotics supplementation is a popular theme to prevent allergies [29], and current available evidence indicates the net benefit of eczema prevention. Likewise, we found probiotics supplementation can mildly influence the risk of allergy. This suggested further research should be conducted to find the detailed causality of probiotics and allergies and maybe indicate the new    prevention method of controlling allergic diseases during pregnancy.
It is worth noting that we found depression and anxiety both had an association with allergies during pregnancy (p = 0.026, p = 0.006 respectively). In accordance with this result, the study in the US [30] and Japan [31]found that food allergy and atopic dermatitis were more common in depressed people. Li et al. [32] reported that anxiety is associated with greater perceived dyspnea in asthma. The literature demonstrated that pregnant women affected by psychological disorders such as anxiety and depression are universal(15.04% and 5.19% [33]), which made a high risk of allergic diseases. Thus doctors and family members should terribly concern about the mental health of pregnant women in order to reduce the threat of allergic diseases.
The data of our study came from following participants in a longitudinal prebirth cohort, obtaining information prospectively. Therefore, we obtained the causal relationship between multiple factors and allergies outcome in a rational chronological order. While some limitations cannot be neglected. To begin with, as a large cohort, loss to follow-up is irresistible for the reasons like spontaneous abortion, withdrawal and move during study, while the sample was representative according to the validation we made before analysis. We would also consider including spontaneous abortion in the first trimester in the subsequent study to explore the influence of them. Secondly, we conducted the cohort for approximately two years and some factors may change during follow-up, which made information biased in the analysis. Further survey about risk or protective factors of allergic diseases and multivariate analysis should continue being carried out. In addition, we were unable to define the different clinical allergic diseases into subtypes despite the outcomes of the participants were confirmed by clinicians.

Conclusion
Our study demonstrated the incidence of allergic diseases in urban pregnant women was 21.0% (95%CI: 20.0% ~ 22.0%), which kept a medium high level, and the relevant factors of allergies during pregnancy contained the history of allergies of pregnant women and their parents, house decoration for less than half a year, exposure to plush toys, disinfectants, insecticides, antihistamines, glucocorticoids, antipyretic analgesics, tocolytic agent, probiotics, self-rated depression and anxiety. Further study had been taken into consideration. Firstly a survey in rural areas would be carried out to investigate the occurrence of allergies in rural pregnant women in China. Next, analysis of risk factors of allergies during pregnancy should be taken to explore the mechanism of allergy in pregnant women. And intervention studies should be conducted to reduce the incidence of maternal allergies.

SGA
Small for gestational age MCH Maternal and child health hospitals Pre-BMI Pre-pregnancy body mass index PHQ-9 Patient health questionnaire 9 GAD-7 Generalized anxiety disorder-7 CI Confidence Intervals